The cells of the normal lung are continuously subject to damage requiring defense and repair activities. High levels of stress and strain on the cells may overload the defense and repair mechanisms and lead to a type of damage ("pre-lesion") which predisposes to overt pathology. Dynamic and subcellular aspects of this pre-lesion state will be studied by electronmicroscopy and tissue culture, using a new methodology developed to stress the cell populations, including nitrogen dioxide exposure of animals and postmortem interval stress (delay in tissue explantation culture). The degree of viability and survival of cells in culture will be a measure of relative cellular susceptibility. Lung cells in culture which are targets of macrophage congregation (M.C.) are being examined by electronmicroscopy for possible involvement in a developmental cycle of an infectious organism, and for cytostructural alterations constituting early or "pre-lesions" resulting from the added stress of NO2 exposure. Histochemical studies, including enzyme activity tests of macrophages and target cells, are concerned with cytostructural features which are related to the M.C. Also, subtypes of macrophages involved in M.C. are apparently distinguished by structural and dynamic properties. The immediate goal is to define cell damage in the absence of overt pathologic lesions, to include common denominators and specific pathways that can lead to "early lesions" of emphysematous, fibrosing and other lung diseases. The ultimate purpose is to assist in the earlier detection, the better treatment and the improved prevention of the major lung diseases through the identification of principal target cells and their fundamental, subcellular injuries. The recognition of particularly vulnerable cells will also be of value in the establishment of air quality standards. BIBLIOGRAPHIC REFERENCES: The influence of 0.4 ppm nitrogen dioxide in vivo on the outgrowth of lung cells in tissue culture; Sherwin, R.P. and Richters, V.; Fed. Proc. 35:632, 1976. Macrophage congregation and influence of nitrogen dioxide: ultrastructural and histochemical aspects; Sherwin, R.P., Richters, V., Bernett, J. and Paller, M.; Accepted, llth Congress of the International Academy of Pathology, 1976.